Blog | Pharma Strategy Blog

Will vemurafenib receive early approval for metastatic melanoma?

By MaverickNY on August 9, 2011

A Reuters press release on vemurafenib (Zelboraf) caught my eye this morning, suggesting that it might be approved in BRAFV600E metastatic melanoma by the FDA might be “imminent” according to an unnamed source and much earlier than the expected PDUFA date in ~~November~~ October 28th (now confirmed by Roche/Genentech).

If so, that’s very good news.

However, what really caught my eye was a quote from a spokesperson at Roche Diagnostics, suggesting that the BRAFV600E test would could around $150. That’s lower than I was expecting, although no doubt it will be considerably offset by the cost of vemurafenib itself.

It was also good to hear recently that Roche and BMS, the manufacturers of ipilimumab (Yervoy), have now met to discuss and finalise the much anticipated combination trial of Zelboraf and Yervoy. It will be interesting to see if the combination will extend survival even further in patients with the V600E mutation. There’s a long way to go before the results bear fruit, as an early dose finding and tolerability study will be the first step in the process.

Of course, pricing and reimbursement will be key, given that Yervoy was launched recently with a $120K price tag for four infusions. On the 2Q earnings call the other week, BMS announced that the launch was going well and uptake was strong. It is given as a 3mg infusion every three weeks for 4 cycles, over a 3 month period. It will be interesting to see what the Zelboraf monthly price will be, assuming it successfully garners approval. Should the combination work out in the future, the cost of treating metastatic melanoma will likely become even more expensive despite only small incremental survival benefits.

2 Comments

Custirsen – a new treatment for castrate resistant prostate cancer?

By MaverickNY on August 8, 2011

I’ve been following the development of Oncogenex’s custirsen for a while based on various posters presented at meetings such as ASCO and AUA, but with the publication of phase II data in prostate cancer, it seems a good time to discuss the compound in more detail.

According to Oncogenex:

“OGX-011, also known as custirsen sodium, inhibits the production of clusterin, a protein that is associated with treatment resistance in a number of solid tumors, including prostate, breast, non-small cell lung, ovarian, and bladder cancers.”

Essentially, I think of it a chemo-enhancer, although more technically, it seems to help delay the onset of resistance developing by targeting clusterin (CLU). CLU is a stress-activated cytoprotective chaperone. It is upregulated by a several cancer drugs and confers resistance when overexpressed.

Low levels of CLU are therefore more desirable and may be useful as a predictive biomarker of response.

Previous data on custirsen from the phase II front-line trial showed an encouraging shift to the right in the survival curves, validating the hypothesis that resistance is delayed:

The current phase II clinical trial received support from both Sanofi and Oncogenex. Results were reported by Saad et al., (2011), who assessed the weekly administration of custirsen in combination with either docetaxel or mitoxantrone in second-line metastatic castrate resistant prostate cancer (CRPC). Patients had previously been treated with a minimum of 2 cycles of a docetaxel-based chemotherapy regimen and progressed during or within 6 months of discontinuation of docetaxel treatment.

Overall, patients (n=42) were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).

What did the data show?

Given that the preclinical in vitro and in vivo models have demonstrated the potential of custirsen to enhance chemotherapy and reduce docetaxel resistance, I was keen to see how the concept would pan out in humans. We all know that preclinical evidence is no guarantee of success in clinical trials! Although the primary goals of the trial were to measure safety and tolerability, the effects on tumour response and disease progression were interesting.

DPC (n=20):

Received: median of eight cycles
Overall survival:15.8 months
TTPP: 10.0 months
10 of 13 (77%) evaluable patients had pain responses
Three of 13 (23%) evaluable patients had objective partial responses
PSA declines of ≥90%, ≥50%, and ≥30% occurred in 4 (20%), 8 (40%) and 11 (55%) patients, respectively.

MPC (n=22):

Received a median of six cycles
Overall survival was 11.5 months
TTPP was 5.2 months
6 of 13 (46%) evaluable patients had pain responses
No objective responses were observed
PSA declines of ≥50% and ≥30% occurred in 6 (27%) and 7 (32%) patients, respectively.

Based on experience, we would expect the results with docetaxel chemotherapy to be better than mitoxantrone, since the latter is only palliative at best.

Additionally, custirsen treatment was shown to significantly decrease levels of the target protein, CLU, and low serum CLU levels during treatment demonstrated superior survival.

Two phase III trials in combination with docetaxel are now ongoing in both the first and second line setting in CRPC. The trials are currently enrolling patients, so results will not be available for a while, ie 2013 at the earliest.

Many of you will remember the video discussion from the American Urological Association meeting earlier this year, where we highlighted the potential for custirsen in combination with an AR antagonist such as MDV3100 from Medivation/Astellas. For those interested, the initial data from the custirsen/MDV3100 combination is shown in the short vlog.

In the meantime, the results look most encouraging, although there is a-ways to go yet, since phase II data is no guarantee of phase III performance.

{Update: Luke Timmerman from Xconomy posted about the slow recruitment to the phase III trials and the protocol amendment to include Sanofi’s cabazitaxel (Jevtana).

References:

Saad, F., Hotte, S., North, S., Eigl, B., Chi, K., Czaykowski, P., Wood, L., Pollack, M., Berry, S., Lattouf, J., Mukherjee, S., Gleave, M., & Winquist, E. (2011). Randomized Phase 2 Trial of Custirsen (OGX-011) with Docetaxel or Mitoxantrone in Patients with Metastatic Castrate-Resistant Prostate Cancer: CUOG Trial P06c Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-11-0859

2 Comments

PTEN is an important tumor suppressor gene in breast cancer

By MaverickNY on August 5, 2011

An interesting new paper has just appeared in the latest online first edition of Cancer Discovery, and discusses a functional classification for evaluating the alterations in breast cancer to ultimately determine which are drivers and passengers.

The researchers are essentially using an integrated approach of combining genomics and gene expression profiles overlaid with functional data to create a systematic map.

The goal was to determine if it will help identify key vulnerabilities in genetic mutations and the breast cancer genome as part of a joint Stand Up To Cancer (SU2C) and American Association for Cancer Research (AACR) initiative.

“We have carried out a functional genetic screen in >30 commonly used models of breast cancer to identify genes critical to the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN-mutated cancers and for estrogen receptor–positive breast cancers.

We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from established subtypes.”

Should such an approach be successful, it is easy to see how it could be replicated in other tumour types.

The beauty of this methodology, while complex, is we know that not all mutations and aberrations that appear are critical to the tumour’s survival, so creating a road map will enable clinicians to better design trials in a more personalised medicine approach to treatment. Once we know a patients particular molecular make up and which aberrations are important, then treatment can be more selective and appropriate based on the profile and biomarkers.

Although conceptually, this article was about the idea of figuring out the critical driver oncogenes, they also focus on PTEN mutations and PIK3CA mutations as potential targets, since loss of PTEN is associated with many cancers, including breast cancer. Unravelling the heterogeneity and key targets amy well lead to new therapeutic approaches.

I first heard of PTEN inhibitors a while back in relation to a small private start-up biotech called Pintex, although they were subsequently sold to a UK company, Vernalis. Vernalis is developing several interesting compounds including Heat-shock proteins (Hsp) and has partnerships with several large pharma companies. I don’t think any of the PTEN inhibitors survived though and it appears to be a transfer of assets that was more valuable than the compounds they had in development.

Since then, the lead PTEN inhibitor appears to be Semafore’s SF1670, which had a recent preclinical publication in Blood magazine (see references below) and may be hitting clinical trials in the next year or two. One interesting approach that might evolve is a ‘set-up-knock-down’ approach in tumours that have loss of PTEN and follow this with, say, a PI3K inhibitor. Semafore also have one of those too, in SF1126, making such a dual strategy in sequencing potentially feasible:

As Michel Becker, Semafore’s acting CEO succinctly described it to me:

“The PTEN inhibitor’s role would be to stimulate quiescent cells into a treatable/PI3K addicted state.”

Check out Wicha et al., (2006) for more details on this concept. Given that PI3K inhibitors have, at best, resulted in stable disease in the tumour types tested to date (including breast cancer), it would be interesting to see if this would lead to better response rates and ultimately, outcomes.

Brough et al’s., (2011) research into loss of PTEN and PIK3CA mutations (mutant not wild type or point mutations) in breast cancer is most interesting, but there is still a long way to go. We need to know more of the underlying biology and the impact of inhibition of targets and the consequences. We should then be able to figure out the optimal targets and logical combination strategies that will lead to responses that are both superior and more durable than currently seen in patients with breast cancer and other tumour types.

The good news is that the basic research is looking fairly promising to date. I can say without hesitation that combination strategies are more likely to lead to better results than targeting either PTEN or PI3K alone.

References:

Brough, R, Frankum, JR, Sims, D, Mackay, A, Mendes-Pereira, AM, Bajrami, I, Costa-Cabral, S, Rafiq, R, Ahmad, AS, Cerone, MA, Natrajan, R, Sharpe, R, Shiu, K-K, Wetterskog, D, Dedes, KJ, Lambros, MB, Rawjee, T, Linardopoulos, S, Reis-Filho, JS, Turner, NC, Lord, CJ, & Ashworth, A (2011). Functional Viability Profiles of Breast Cancer. Cancer Discovery : 10.1158/2159-8290.CD-11-0107

Li, Y., Prasad, A., Jia, Y., Roy, S., Loison, F., Mondal, S., Kocjan, P., Silberstein, L., Ding, S., & Luo, H. (2011). Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model. Blood, 117 (24), 6702-6713 DOI: 10.1182/blood-2010-09-309864

Wicha, M. (2006). Cancer Stem Cells: An Old Idea–A Paradigm Shift Cancer Research, 66 (4), 1883-1890 DOI: 10.1158/0008-5472.CAN-05-3153

How picking up prostate cancer earlier may improve outcomes

By MaverickNY on August 4, 2011

Prostate cancer is very much in the news this morning, not all for good reasons though.

Dendreon’s Provenge launch to community oncologists did not go well

Dendreon’s stock is in free fall after the company missed it’s earnings and revenue expectations rather badly yesterday. Adam Feuerstein of The Street has a nice overview of the 2Q earnings call for those of you interested.

There are a couple of things that come to mind though:

The reimbursement may well have a broader impact on the landscape than many realise – CMS may pay for a drug or vaccine, but it doesn’t always pay for the surrounding expenses associated with it*
The “cost dense” issue is offset by ipilimumab (Yervoy) doing better than expected in their metastatic melanoma launch despite a higher overall price (execution matters!)
The root of Dendreon’s problem may well be lack of demand and healthy scepticism from medical oncologists over the value of Provenge relative to the cost:benefit (no impact on tumour shrinkage, bone pain, etc; patients just live a little longer)
Strategy and execution are key in cancer launches to community oncologists

* There are some excellent reimbursement experts out there such as my good friend Bobbi Buell at Covad who steer companies through this kind of minefield. In fair disclosure, I know I appreciated and valued her solid advice when I was at Novartis and we launched Gleevec in CML. Having such expertise is a necessity, not a luxury, these days.

Medivation’s MDV3100 may have new opportunities

There was good news from Medivation that caught my interest. Medivation are developing their androgen receptor (AR) antagonist, MDV3100, in castrate resistant prostate cancer pre and post chemotherapy, with interim results from the latter possibly expected by the year end. Today, the company announced some positive preclinical data in breast cancer:

“Researchers at the University of Colorado Denver… provide evidence that MDV3100 inhibits proliferation of breast cancer cells.

In different cell-based assays, MDV3100 was able to inhibit both androgen- and estrogen-mediated breast cancer cell proliferation.”

What are the significance of these findings? Well, the company quoted one of the study authors, Dr Jennifer Richter:

“Our findings are exciting because they challenge the existing idea that androgens are protective in breast cancer by demonstrating that androgens can stimulate proliferation of breast cancer.

These preclinical data show that MDV3100 suppresses androgen-driven breast cancer cell growth and, surprisingly, also suppresses estrogen-driven breast cancer cell growth.”

I think it would be reasonable to expect a phase I clinical trial to evolve soon to test the hypothesis in women with hormone-sensitive breast cancer.

TMPRSS2:ERG may be a more useful marker than PSA in prostate cancer

The big news that really cheered me most this morning, though, was new data from Science Translational Medicine showing the feasibility of a simple urine test to pick up signs of prostate cancer potentially earlier than we do now. Having had a father who was suddenly diagnosed with stage IV disease, hearing about a test that may help diagnose it earlier than currently feasible with biopsies or PSA is a most welcome advance.

Back in 2005, Arul Chinnaiyan’s lab reported a fusion between two genes present in around half of all prostate cancers called TMPRSS2:ERG. When the two genes, TMPRSS2 and ERG, combine, they cause aberrant activity and drive prostate cells to grow out of control, leading to cancer. This is in much in the same way BCR-ABL drives aberrant activity in chronic myeloid leukemia (CML). The next step after the discovery was to evaluate the reliability and faithfulness of the gene in indicating whether men had prostate cancer.

In the latest report, the researchers measured the level of the fused gene in the urine of men (n=1312) with high PSA levels in their blood, then looked at TMPRSS2:ERG levels, tumour volume and clinically significant prostate cancer, and PCA levels. They analysed the data to see if the two markers were a good indication of prostate cancer or not.

Half of the men sampled were found to have the TMPRSS2:ERG gene, confirming previous research by the group.

The results also demonstrated:

“TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy.”

Essentially, this means that by combining the TMPRSS2:ERG results with PCA data, the group have found a way to stratify men with prostate cancer in terms of risk – in other words, they have a larger and more invasive tumour that requires aggressive treatment.

The diagnostic technology was developed by Gen-Probe, so I think it would be reasonable to assume the company will submit the data to the FDA for approval once further tests have been completed to evaluate accuracy and specificity of the test. If those are successful, we may well have a new diagnostic test for prostate cancer in the not too distant future.

It goes without saying that picking up aggressive disease earlier and treating it effectively will likely lead to better outcomes for men with prostate cancer.

References:

Tomlins, S., Aubin, S., Siddiqui, J., Lonigro, R., Sefton-Miller, L., Miick, S., Williamsen, S., Hodge, P., Meinke, J., Blase, A., Penabella, Y., Day, J., Varambally, R., Han, B., Wood, D., Wang, L., Sanda, M., Rubin, M., Rhodes, D., Hollenbeck, B., Sakamoto, K., Silberstein, J., Fradet, Y., Amberson, J., Meyers, S., Palanisamy, N., Rittenhouse, H., Wei, J., Groskopf, J., & Chinnaiyan, A. (2011). Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA Science Translational Medicine, 3 (94), 94-94 DOI: 10.1126/scitranslmed.3001970

1 Comment

Pharma and Social Media: Update on abiraterone in advanced prostate cancer

By MaverickNY on August 3, 2011

“Fully 71% of online Americans use video-sharing sites such as YouTube and Vimeo, up from 66% a year earlier. The use of video-sharing sites on any given day also jumped five percentage points, from 23% of online Americans in May 2010 to 28% in May 2011.”

Pew Internet (2011)

This is a trend I’ve also noticed amongst my friends over the past year, largely driven by more of them using smartphones and iPads, which make sharing and watching video a whole lot easier.

In the past, I’ve been rather frustrated with Pharmaland and their resolutely horrid web 1.0 branded and unbranded websites that have tiny text, are heavy on flash or not mobile optimised, making sharing or even reading challenging, especially on mobile gadgets. Watching a useful video online, but not being able to share it on Twitter or Facebook with others, is one of those typical desk bang moments – why not if you can share the link to the website? The world has moved on in terms of how we interact with websites and people online.

Thus I usually end up clicking out and forgetting about them altogether, unless I really need the Prescribing Information (PI) and have to spend a few minutes scrolling and hunting down a miniscule small link that is almost impossible to click without hitting the adjacent link next to it.

Then every once in while something beautiful comes along…

Yesterday, someone outside the US emailed me asking about access to abiraterone (Zytiga) outside the US, so I went on my iPad and to my delight and surprise found this on the Healthcare Professionals page:

Several key points to note here:

You can share information with others by email and Twitter
The PI was easy to find and click on
The mechanism of action (MOA) video on Vimeo was high quality, interesting and sharable
You can sign up for updates or view press releases easily
The reimbursement support information was also easy to access
The UI is uncluttered, has nice large text and is easy to navigate at a glance

In fact, the whole site was nicely laid out and easy to see things, click where you need to go and navigate with the well-thought out UI. I didn’t have to pinch the screen once, which made a nice change.

Now, there are some glitches such as the patient information was a bit sparse and clicking the Contact Us section took me to the main Janssen website rather than a contact page, forcing me to scroll around looking for it there (hidden at the bottom in pale grey). There’s no international number or email address when you finally find it, leaving me wondering what to advise my reader who contacted me for help. This is where providing global Expanded Access Programs or local country contact details can be helpful – they will inevitably reach out, so not providing any help online is a tad antisocial. There is more than just USA patients with advanced prostate cancer out there, after all.

If anyone from Janssen or Ortho Biotech Global is reading this and could point me in the right direction for helping patients and caregiver outside the US that would be great, as several enquiries a month come in on this topic. There’s nothing worse than no information or not being able to help. Companies ultimately live or die on seamless customer service and helping people with their needs.

The experience was pretty positive and I really liked the abiraterone website – it’s a good example of how nice UI design can make a huge difference to the UX for those visiting. Whichever digital agency was responsible for this site did a very nice job so far and it breaks the cluttered, awkward to navigate with uncomfortably tiny font product website one normally comes across in this field – well done!

I’m hoping the Patient section will soon have some useful information to rival the HCP portal. Putting in country contact details will be a good start in the right direction, as will information about ongoing clinical trials and a well designed, easy to read patient brochure about the disease, treatment and reimbursement information. Yes – they do ask about the price and how they can save money – we get emails on that very topic every month too.

An excellent start overall – looking forward to seeing more developments in the near future!

The role of PTEN in non-melanoma skin cancer

By MaverickNY on August 1, 2011

While reading the latest Cancer Research journal, I was surprised to learn that:

“Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor.”

Ming et al., (2011)

In fact, more than one million new cases are diagnosed in the US annually, which accounts for 40% of all new cancer cases. That’s a lot of skin cancer!

Source: s_manca: Great Barrier Reef

The bigger question, though, is what are the genetic underpinings of the disease? These non-melanoma skin skin cancers tend to derive from the epidermal basal layer in response to DNA damage from sunlight.

From an incidence perspective, I would suspect that those with pale skin who are subject to harsh sunlight such as Australia would be particularly susceptible.

Researchers from the University of Chicago may have identified a role for PTEN, a known tumour suppressor, in removing DNA damage derived from UVB radiation, see Ming et al., (2011) in the references below. UVB radiation is a known risk factor for non-melanoma skin cancer.

In previous research, the group discovered laboratory mice with reduced levels of PTEN were more likely to have UVB-induced skin cancers. They therefore decided to test the idea in human cells to see if the finding could be replicated.

In the latest research, they reported what happened when they exposed skin cells to UVB radiation and examined the rates of DNA repair. Those with lower PTEN levels had slower rates of DNA repair, because of loss of the key DNA repair protein xeroderma pigmentosum C (XPC).

What was most interesting was what happened when the scientists restored the levels of XPC? In that situation, the rates of DNA repair went up as well.

Overall, the current research in human cell lines suggests that cells without adequate levels of PTEN were not able to repair sufficiently, confirming the results seen in the mice.

Given a greater understanding of the molecular mechanisms underpining non-melanoma skin cancer potentially means that chemoprevention strategies can be developed down the road. In other words, if we could identify those most at risk due to low PTEN levels, then supplements or therapeutics might be useful as a protection strategy.

Photo Credit: s_manca

References:

Ming, M., Feng, L., Shea, C., Soltani, K., Zhao, B., Han, W., Smart, R., Trempus, C., & He, Y. (2011). PTEN Positively Regulates UVB-Induced DNA Damage Repair Cancer Research, 71 (15), 5287-5295 DOI: 10.1158/0008-5472.CAN-10-4614

1 Comment

New solutions for resistance to therapies in lung cancer?

By MaverickNY on July 29, 2011

One of the things that is both frustrating and fascinating is the development of resistance to therapies in cancer treatment. By this, I mean clearly it’s not something we want to see from a patient or physician perspective and if possible, to delay it as long as feasible. On the other hand, the mechanics behind the biology of drug resistance is a fertile field for curious scientists.

I never fail to feel a sense of awe when a group cracks open new mechanisms that improve our understanding of cancer. It is, after all, a highly complex and fickle topic. I’ve often wondered why is it that some patients see resistance set in early and others do not? Why does resistance occur, period?

This morning my interest was piqued by a new paper published this month in Science Translational Medicine from William Pao’s group at Vanderbilt. They looked at the conundrum around EGFR inhibitors such as erlotinib, gefitinib and afatinib in non-small cell lung cancer (NSCLC) because patients treated with these drugs eventually develop acquired resistance to therapy and the cancer unfortunately starts growing again. The big question are why and what?

“The most common mechanism of resistance is a second site mutation within exon 20 of EGFR (T790M), observed in ~50% of cases. This change leads to altered binding of the drug within the ATP pocket.”

In this elegant research, they looked at the behaviour in cell lines before and after the cells acquire resistance to targeted therapy:

“Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance.

To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors.”

What they found was really interesting

In simple terms, they noticed that NSCLC cells grow at different rates, which may possibly explain why some tumours become resistant to EGFR inhibitors faster than others.

What was surprising though, is that EGFR mutant (resistant) cells grew at a slower rate:

“On average, parental cells doubled ~1.22 times faster than T790M-containing resistant cells.”

It isn’t yet clear why this happens though.

In clinical practice, it has been noticed that patients with acquired resistance have re-responded to tyrosine kinase inhibitor (TKI) therapy after a drug holiday. Chmielecki et al., found some evidence as to why this might happen, since they observed that:

“Lysates from parental cells and late-passage PC-9/BR–resistant cells treated with BIBW-2992 showed significantly reduced phosphorylation of EGFR and its downstream targets, extracellular signal–regulated kinase (ERK) and AKT, whereas lysates from resistant cells maintained in the presence of TKI and treated with the same concentrations of drug did not.”

Once the validity of the preclinical findings were established, they looked at evolutionary modelling to design optimal dosing strategies for the use of EGFR inhibitors in NSCLC. They incorporated PK data from clinical trials to ensure the drug doses proposed were feasible. The modelling appeared to be useful:

“This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance.”

It is worth noting the strategy predicted by the model:

“We propose the use of high-dose pulsed once-weekly BIBW-2992 with daily low-dose erlotinib to delay the emergence of T790M-mediated resistance. PC-9 cells treated with this regimen required twice as long to develop resistance and did not show selection for T790M mutations.

In patients, the combination of two EGFR TKIs could lead to overlapping toxicities involving rash and diarrhea. Thus, in a phase IB dose-safety trial, we would recommend a more tolerable strategy, with lower doses of erlotinib still known to be effective against EGFR-mutant tumors (25 or 50 mg daily, orally).”

What’s also fascinating to me is that the overall study findings make sense for consideration when using other TKIs as well, since we know that GIST patients treated with imatinib can re-respond after a period of drug holiday (see Fumagalli et al., (2009). Could different dosing strategies be adopted in some patients at a high risk of developing resistance based on the model approach?

It will be most interesting to see whether clinical trials in lung cancer with EGFR inhibitors evolve along the lines of those suggested by the researchers – that will be the ultimate proof of the pudding that resistance can be influenced in patients with NSCLC – until then, it’s a valuable hypothesis.

References:

Chmielecki, J., Foo, J., Oxnard, G., Hutchinson, K., Ohashi, K., Somwar, R., Wang, L., Amato, K., Arcila, M., Sos, M., Socci, N., Viale, A., de Stanchina, E., Ginsberg, M., Thomas, R., Kris, M., Inoue, A., Ladanyi, M., Miller, V., Michor, F., & Pao, W. (2011). Optimization of Dosing for EGFR-Mutant Non-Small Cell Lung Cancer with Evolutionary Cancer Modeling. Science Translational Medicine, 3 (90), 90-90 DOI: 10.1126/scitranslmed.3002356

E. Fumagalli, P. Coco, C. Morosi, P. Dileo, R. Bertulli, A. Gronchi, & P. G. Casali (2009). Rechallenge with imatinib in GIST patients resistant to second or third line therapy 15th Connective Tissue Oncology Society Meeting, Miami Beach, FL

3 Comments

Try something new for 30 days

By MaverickNY on July 27, 2011

Recently, I was inspired by Google’s Matt Cutts TED talk on how he made a few simple changes in his lifestyle and tried them for 30 days. With the tendency to be more desk bound as a consultant, I have found more weight has slowly crept on, much to my dismay, which is not good for general health and well being. I decided to do something about it.

My goals were to:

do more walking (an hour a day)
eat smaller portions
cut out sugar
get outside more
experiment with a new work flow using some tools and apps I recently signed up for.

So far this month, the plan is doing well. In Boston last week, for example, I probably walked more in 4 days than I had in the previous 2 months! I’m now thinking of getting a Fitbit and recording my exercise/step levels to see what impact that has.

The video is well worth watching and only 3.5 mins long – check it out!

What health and well being changes are you making in your life?

6 Comments

On mTOR and Tuberosis Sclerosis Complex (TSC)

By MaverickNY on July 26, 2011

It’s that time of year in the dog days of summer when many people in the industry are either incredibly busy, heads down, rolling out new things for the third quarter or else it’s a pleasant lull between the strategic and tactical phases and a good time to catch your breath. Here in the Icarus office, we’re busy creating and writing a new series of syndicated reports in a variety of different tumour types and pathways. I have hundreds of snippets and notes saved electronically from various cancer meetings this year, making it a great opportunity to collate and process them into broader insights. If you have any particular needs in this area, now is a good time to let us know, so do email me and your wishes may get added to the list.

Last week I was in Boston and happened by chance to walk past the Whitehead Institute. This reminded me that I had David Sabatini’s new mTOR paper in Science queued up to blog about on Pharma Strategy Blog.

The mTOR pathway is highly complex and consists of a huge network of interwined proteins and kinases:

Source: wikipedia

Hsu et al., (2011) described what they found from defining the mTOR-regulated phosphoproteome using quantitative mass spectrometry and protein libraries to build a complete picture:

“The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1.

Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.”

We know, for example, that mTORC1 inhibits PI3K-Akt signaling, but the precise molecular connections involved are poorly understood. S6K1 phophosphorylation, which destabilises the insulin receptor substrate 1 (IRS1), is one mechanism known to be involved. Hsu et al., demonstrated that other mechanisms are also critical:

“mTORC1 inhibits and destabilizes IRS1 and simultaneously activates and stabilizes Grb10.”

They went to separate the effects of acute and chronic stimulation of mTOR:

“Whereas acute mTORC1 inhibition leads to dephosphorylation of IRS1 and Grb10, chronic mTORC1 inhibition leads to changes in the abundance of IRS and Grb10 proteins, which are likely the most important effects of mTOR inhibitors to consider in their clinical use.”

This important article is particularly relevant because not long after the publication, Novartis announced positive data with their mTOR inhibitor, everolimus (Afinitor) in patients with tuberous sclerosis complex (TSC).

TSC is a genetic disorder that affects affects approximately 1-2 million people worldwide and is associated with a variety of resulting disorders including seizures, swelling in the brain, developmental delays and skin lesions. It can also cause non-cancerous tumours to form and can affect many different parts of the body such as the brain and kidney, for example.

The rationale behind such as study was described in the Novartis press release:

“Tuberous sclerosis complex is caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR activity is increased, which can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism, leading to the formation of non-cancerous tumors throughout the body, including the brain.”

In other words, giving an mTOR inhibitor such as everolimus may help by reduce cell proliferation, blood vessel growth and glucose uptake associated with the TSC defect.

In patients with brain lesions, surgery is usually considered the only viable option, so a study showing a 35% response rate (50% reduction or more) in the SEGA lesions, is a positive step forward. The new data was from a phase III trial (n=117) and appears to support the initial positive phase II study, so it will likely lead to a registration filing in this indication for everolimus.

References:

Hsu, P., Kang, S., Rameseder, J., Zhang, Y., Ottina, K., Lim, D., Peterson, T., Choi, Y., Gray, N., Yaffe, M., Marto, J., & Sabatini, D. (2011). The mTOR-Regulated Phosphoproteome Reveals a Mechanism of mTORC1-Mediated Inhibition of Growth Factor Signaling. Science, 332 (6035), 1317-1322 DOI: 10.1126/science.1199498